A common attitude in natural products research is that nuclear magnetic resonance (NMR) spectroscopy serves as a primary tool,
whereas mass spectrometry (MS) is relegated to the task of providing the molecular formulas of pure compounds. Yet over the
past several decades, we have witnessed astonishing growth in MS. Electrospray ionization has enabled the analysis of biological
molecules previously deemed intractable, and instruments that offer astounding mass accuracy are becoming routinely available.
Nonetheless, as applied to natural products research, MS is still fraught with challenges and pitfalls. Here is an account
of strategies to conduct effective research despite these obstacles.
Among natural products chemists there is a joke that goes like this: Nuclear magnetic resonance (NMR) spectroscopy is like
your mother; she knows what is good for you and tells you what you need to hear. Mass spectrometry (MS) is like your lover,
willing to say whatever you want to hear whether it is true or not.
This joke reflects a common attitude in natural products research; NMR serves as a primary tool, whereas MS is relegated to
the task of providing the molecular formulas of pure compounds. Yet over the past several decades, we have witnessed astonishing
growth in MS. Electrospray ionization (ESI) has enabled the analysis of biological molecules previously deemed intractable,
and instruments that offer astounding mass accuracy are becoming routinely available. Nonetheless, as applied to natural products
research, MS is still fraught with challenges and pitfalls. What follows is an account of the strategies that my laboratory
(and those of colleagues and collaborators) espouse to conduct effective research despite these obstacles. In this column,
I have tried to paint an honest picture of what we actually do (and don't do) in the laboratory rather than what is theoretically
possible. As such, this account reflects my own perspective and opinions. By no means do I present it as the only (or last)
word on the topic.
MS for Structure Elucidation
Natural products research is primarily concerned with identifying useful compounds from natural sources, including plants,
fungi, bacteria, and marine organisms. These organisms share the common characteristic of being complex mixtures of thousands
of structurally diverse molecules present at varying abundance (1). (Note that reference 1 describes a typical plant extract
mixture in which there are estimated to be 920 compounds theoretically detectable by a given liquid chromatography with ultraviolet
absorbance detection [LC–UV] method. These represent only a subset of the compounds present in the mixture.) Natural products
chemists seek to unravel this complexity and distill it to the key active elements that contribute to a desired effect. Thus,
we isolate anti-inflammatory compounds from marine sponges, insecticidal compounds from fungi, or antimicrobial compounds
from traditional plant-derived medicines.
Like many scientists educated in the 1990s, I can thank Sean Connery — or, more precisely, his character in the film "Medicine
Man" — for my introduction to natural products research. Those acquainted with this classic may recall a scene in which a
cancer-curing natural product mixture is injected into a portable gas chromatography–mass spectrometry (GC–MS) system, which,
having been transported by canoe, miraculously operates in the midst of the jungle on generator-provided power. Within seconds,
the structure, including stereochemistry, of a new molecule responsible for the biological activity of this mixture appears
on a blinking LED screen. Fantastic as it seems even by 2013 standards, this scenario could represent the holy grail of natural
products research. Such an instrument — portable and able to elucidate the structure of components in a mixture without the
need for user intervention or pure standards — would revolutionize our field, not to mention all of chemistry and biology.
Regrettably, analytical equipment of such awesome capability does not currently exist. The tool that comes closest, however,
is the mass spectrometer.